IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Satoshi Kofuji, Akiyoshi Hirayama, Alexander Otto Eberhardt, Risa Kawaguchi, Yuki Sugiura, Oltea Sampetrean, Yoshiki Ikeda, Mikako Warren, Naoya Sakamoto, Shuji Kitahara, Hirofumi Yoshino, Daisuke Yamashita, Kazutaka Sumita, Kara Wolfe, Lisa Lange, Satsuki Ikeda, Hiroko Shimada, Noriaki Minami, Akshiv Malhotra, Shin MoriokaYuki Ban, Maya Asano, Victoria L. Flanary, Annmarie Ramkissoon, Lionel M.L. Chow, Juri Kiyokawa, Tomoyuki Mashimo, Greg Lucey, Sergey Mareninov, Tatsuya Ozawa, Nobuyuki Onishi, Koichi Okumura, Jumpei Terakawa, Takiko Daikoku, Trisha Wise-Draper, Nazanin Majd, Kaori Kofuji, Mika Sasaki, Masaru Mori, Yonehiro Kanemura, Eric P. Smith, Dimitrios Anastasiou, Hiroaki Wakimoto, Eric C. Holland, William H. Yong, Craig Horbinski, Ichiro Nakano, Ralph J. DeBerardinis, Robert M. Bachoo, Paul S. Mischel, Wataru Yasui, Makoto Suematsu, Hideyuki Saya, Tomoyoshi Soga, Ingrid Grummt, Holger Bierhoff, Atsuo T. Sasaki

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

Original languageEnglish (US)
Pages (from-to)1003-1014
Number of pages12
JournalNature Cell Biology
Volume21
Issue number8
DOIs
StatePublished - Aug 1 2019

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IMP Dehydrogenase
Glioblastoma
Carcinogenesis
Transfer RNA
Guanine Nucleotides
Nuclear Proteins
GTP-Binding Proteins
Brain Neoplasms
Neuroglia
Hypertrophy
Up-Regulation
Cell Proliferation
Pharmacology
Enzymes
Growth
Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kofuji, S., Hirayama, A., Eberhardt, A. O., Kawaguchi, R., Sugiura, Y., Sampetrean, O., ... Sasaki, A. T. (2019). IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma. Nature Cell Biology, 21(8), 1003-1014. https://doi.org/10.1038/s41556-019-0363-9

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma. / Kofuji, Satoshi; Hirayama, Akiyoshi; Eberhardt, Alexander Otto; Kawaguchi, Risa; Sugiura, Yuki; Sampetrean, Oltea; Ikeda, Yoshiki; Warren, Mikako; Sakamoto, Naoya; Kitahara, Shuji; Yoshino, Hirofumi; Yamashita, Daisuke; Sumita, Kazutaka; Wolfe, Kara; Lange, Lisa; Ikeda, Satsuki; Shimada, Hiroko; Minami, Noriaki; Malhotra, Akshiv; Morioka, Shin; Ban, Yuki; Asano, Maya; Flanary, Victoria L.; Ramkissoon, Annmarie; Chow, Lionel M.L.; Kiyokawa, Juri; Mashimo, Tomoyuki; Lucey, Greg; Mareninov, Sergey; Ozawa, Tatsuya; Onishi, Nobuyuki; Okumura, Koichi; Terakawa, Jumpei; Daikoku, Takiko; Wise-Draper, Trisha; Majd, Nazanin; Kofuji, Kaori; Sasaki, Mika; Mori, Masaru; Kanemura, Yonehiro; Smith, Eric P.; Anastasiou, Dimitrios; Wakimoto, Hiroaki; Holland, Eric C.; Yong, William H.; Horbinski, Craig; Nakano, Ichiro; DeBerardinis, Ralph J.; Bachoo, Robert M.; Mischel, Paul S.; Yasui, Wataru; Suematsu, Makoto; Saya, Hideyuki; Soga, Tomoyoshi; Grummt, Ingrid; Bierhoff, Holger; Sasaki, Atsuo T.

In: Nature Cell Biology, Vol. 21, No. 8, 01.08.2019, p. 1003-1014.

Research output: Contribution to journalArticle

Kofuji, S, Hirayama, A, Eberhardt, AO, Kawaguchi, R, Sugiura, Y, Sampetrean, O, Ikeda, Y, Warren, M, Sakamoto, N, Kitahara, S, Yoshino, H, Yamashita, D, Sumita, K, Wolfe, K, Lange, L, Ikeda, S, Shimada, H, Minami, N, Malhotra, A, Morioka, S, Ban, Y, Asano, M, Flanary, VL, Ramkissoon, A, Chow, LML, Kiyokawa, J, Mashimo, T, Lucey, G, Mareninov, S, Ozawa, T, Onishi, N, Okumura, K, Terakawa, J, Daikoku, T, Wise-Draper, T, Majd, N, Kofuji, K, Sasaki, M, Mori, M, Kanemura, Y, Smith, EP, Anastasiou, D, Wakimoto, H, Holland, EC, Yong, WH, Horbinski, C, Nakano, I, DeBerardinis, RJ, Bachoo, RM, Mischel, PS, Yasui, W, Suematsu, M, Saya, H, Soga, T, Grummt, I, Bierhoff, H & Sasaki, AT 2019, 'IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma', Nature Cell Biology, vol. 21, no. 8, pp. 1003-1014. https://doi.org/10.1038/s41556-019-0363-9
Kofuji S, Hirayama A, Eberhardt AO, Kawaguchi R, Sugiura Y, Sampetrean O et al. IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma. Nature Cell Biology. 2019 Aug 1;21(8):1003-1014. https://doi.org/10.1038/s41556-019-0363-9
Kofuji, Satoshi ; Hirayama, Akiyoshi ; Eberhardt, Alexander Otto ; Kawaguchi, Risa ; Sugiura, Yuki ; Sampetrean, Oltea ; Ikeda, Yoshiki ; Warren, Mikako ; Sakamoto, Naoya ; Kitahara, Shuji ; Yoshino, Hirofumi ; Yamashita, Daisuke ; Sumita, Kazutaka ; Wolfe, Kara ; Lange, Lisa ; Ikeda, Satsuki ; Shimada, Hiroko ; Minami, Noriaki ; Malhotra, Akshiv ; Morioka, Shin ; Ban, Yuki ; Asano, Maya ; Flanary, Victoria L. ; Ramkissoon, Annmarie ; Chow, Lionel M.L. ; Kiyokawa, Juri ; Mashimo, Tomoyuki ; Lucey, Greg ; Mareninov, Sergey ; Ozawa, Tatsuya ; Onishi, Nobuyuki ; Okumura, Koichi ; Terakawa, Jumpei ; Daikoku, Takiko ; Wise-Draper, Trisha ; Majd, Nazanin ; Kofuji, Kaori ; Sasaki, Mika ; Mori, Masaru ; Kanemura, Yonehiro ; Smith, Eric P. ; Anastasiou, Dimitrios ; Wakimoto, Hiroaki ; Holland, Eric C. ; Yong, William H. ; Horbinski, Craig ; Nakano, Ichiro ; DeBerardinis, Ralph J. ; Bachoo, Robert M. ; Mischel, Paul S. ; Yasui, Wataru ; Suematsu, Makoto ; Saya, Hideyuki ; Soga, Tomoyoshi ; Grummt, Ingrid ; Bierhoff, Holger ; Sasaki, Atsuo T. / IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma. In: Nature Cell Biology. 2019 ; Vol. 21, No. 8. pp. 1003-1014.
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abstract = "In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.",
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AU - Hirayama, Akiyoshi

AU - Eberhardt, Alexander Otto

AU - Kawaguchi, Risa

AU - Sugiura, Yuki

AU - Sampetrean, Oltea

AU - Ikeda, Yoshiki

AU - Warren, Mikako

AU - Sakamoto, Naoya

AU - Kitahara, Shuji

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AU - Yamashita, Daisuke

AU - Sumita, Kazutaka

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AU - Ikeda, Satsuki

AU - Shimada, Hiroko

AU - Minami, Noriaki

AU - Malhotra, Akshiv

AU - Morioka, Shin

AU - Ban, Yuki

AU - Asano, Maya

AU - Flanary, Victoria L.

AU - Ramkissoon, Annmarie

AU - Chow, Lionel M.L.

AU - Kiyokawa, Juri

AU - Mashimo, Tomoyuki

AU - Lucey, Greg

AU - Mareninov, Sergey

AU - Ozawa, Tatsuya

AU - Onishi, Nobuyuki

AU - Okumura, Koichi

AU - Terakawa, Jumpei

AU - Daikoku, Takiko

AU - Wise-Draper, Trisha

AU - Majd, Nazanin

AU - Kofuji, Kaori

AU - Sasaki, Mika

AU - Mori, Masaru

AU - Kanemura, Yonehiro

AU - Smith, Eric P.

AU - Anastasiou, Dimitrios

AU - Wakimoto, Hiroaki

AU - Holland, Eric C.

AU - Yong, William H.

AU - Horbinski, Craig

AU - Nakano, Ichiro

AU - DeBerardinis, Ralph J.

AU - Bachoo, Robert M.

AU - Mischel, Paul S.

AU - Yasui, Wataru

AU - Suematsu, Makoto

AU - Saya, Hideyuki

AU - Soga, Tomoyoshi

AU - Grummt, Ingrid

AU - Bierhoff, Holger

AU - Sasaki, Atsuo T.

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AB - In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

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